Glaucoma is a disease characterized by visual field loss as a result of the death of retinal ganglion cells. Although increased intraocular pressure remains the most clearly defined risk factor for glaucoma, it is becoming clear that a wide range of other factors can also lead to ganglion cell loss. Pharmacological or surgical regulation of intraocular pressure can stabilize many patients but for some there is still a progressive loss of vision. Thus, there is an urgent need to develop new rational strategies to slow or prevent neuronal loss occurring in glaucoma. There is abundant evidence that the eye, like other regions of the CNS, contains endogenous neurotrophic/neuroprotective factors that function to limit cell injury. It is the basic premise of this proposal that these neuroprotective mechanisms can be exploited to prevent much of the cell death associated with diseases such as glaucoma. This proposal focuses on one neuroprotective molecule, CNTF, a factor that has already been shown to have potent neuroprotective effects in a number of CNS regions including the retina and is a leading candidate for slowing the progression of ganglion cell loss. In our preliminary data we present evidence that CNTF supports the survival of purified rat RGCs in low density cultures and that its downstream effector STAT3 prevents RGCs from degenerating in ischemia- reperfusion injury. We now propose a series of experiments to test if RGCs can be prevented from dying in the presence of toxic levels of glutamate by CNTF. In a first aim we will define the pathways used by CNTF to exert its protective action. Second, we will examine whether Muller glia can respond to CNTF and provide synergistic protection to RGCs by the secretion of additional neuroprotective factors or a range of other responses. Finally we will test whether the protective pathways activated by CNTF lead to a reduction in reactive oxygen species generation by mitochondria through the activation of mitochondrial uncoupling proteins. PUBLIC HEALTH RELEVANCE: Glaucoma is a blinding disease that affects over 65 million people worldwide. There is still not a good understanding of the basic biochemical mechanisms which cause the death of retinal cells and subsequent loss of vision. This research will identify some of these biochemical pathways. The results of this research will lead to the identification of target molecules for which new therapeutic drugs can be designed.